This proposal seeks to develop an understanding on the genetic and biochemical mechanisms governing mucoidy and virulence in P. aeruginosa which infect respiratory tracts of cystic fibrosis (CF) patients. It is proposed that the mucoid Pseudomonas harbors genes presumably on a phage genome or a large plasmid (Extrachromosomal Element, EE), which code for degradative enzymes active on certain abnormal host mucus glycoproteins. These abnormal glycoprotein(s) are absent in non-CF sputum and accumulate only at certain stages of the CF disease. Accumulation of such abnormal glycoprotein(s) will trigger Pseudomonas infection, since the presumptive Pseudomonas EE can specify not only the degradative enzymes for these abnormal glycoproteins, but also encode enzymes that can utilize the host mucus glycoprotein breakdown products (sugars) to form GDP - mannuronic acid. The EE may also specify the nucleotide-sugar transferase enzymes that can transfer the GDP-mannuronic acid units to a core oligosaccharide, leading to the biosynthesis of mannuronic acid polymers. An epimerase (C5) may then convert some mannuronic acid residues to guluronic acid on the polysaccharide itself. The exopolysaccharide is believed to have specific affinities for some receptor sites on CF bronchial epithelial cells, so that the mucoid cells can preferentially colonize the CF respiratory tissues. Since the bacterial exopolysaccharide production is dependent on host abnormal glycoprotein degradation, it is clear that no colonization will take place until the abnormal glycoproteins start to accumulate. Aditionally, the mucoid cells may elaborate virulence factors that contribute to tissue damage. The use of sugar analogues, or inhibitors that interfere with host mucus breakdown, specific adhesion, or polysaccharide biosynthesis, may thus help eliminate Pseudomonas infection in CF patients.